title: A novel antioxidant 3,7-dihydroxy-isoflav-3-ene (DHIF) inhibits neointimal hyperplasia after vessel injury attenuating reactive oxygen species and nuclear factor-kappaB signaling.
abstract: Reactive oxygen species (ROS) contribute to neointimal smooth muscle proliferation by yet to be defined mechanisms. We examined the effects of a novel isoflavone 3,7-dihydroxy-isoflav-3-ene (DHIF) on development of neointimal lesions in relation to ROS elevations and cell signaling in injured arteries. Carotid arteries of rabbits treated with vehicle or DHIF were injured with a balloon catheter and effects on proliferation, apoptosis, vessel structure, ROS, NF-kappaB activation, cyclooxygenase and gene expression examined. Seven days after injury proliferating neointimal cells were reduced by 35% (P<0.05) whilst medial cell proliferation was attenuated by 16% (P<0.05). ROS levels were elevated fourfold in injured arteries of vehicle-treated rabbits. Treatment with DHIF prevented this elevation (P<0.05). Also, NF-kappaB was activated in neointimal cells from vehicle-treated rabbits, demonstrated by nuclear accumulation of NF-kappaB-p65. DHIF not only attenuated its nuclear accumulation but also suppressed NF-kappaB-p65 expression in neointimal cells. This was accompanied by a doubling of apoptotic cell numbers (P<0.05). Expression of cyclooxygenases Cox-1 and Cox-2 were also attenuated, by 74% and 50%, respectively (P<0.05), as was MCP-1. The antiproliferative effects of DHIF persisted at 14 days, and 28 days after injury neointima growth was attenuated by 50% (P<0.05). Thus, ROS stimulates neointima growth via mechanisms involving NF-kappaB activation, cyclooxygenases and MCP-1. DHIF's ability to attenuate NF-kappaB activation suggests that it may not only be useful in preventing restenosis but also in attenuating atherosclerosis.
authors.affiliation: Baker Heart Research Institute, Melbourne, Victoria, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Kanellakis
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pomilio
authors.forename: Catherine
authors.initials: C
authors.lastname: Walker
authors.forename: Alan
authors.initials: A
authors.lastname: Husband
authors.forename: Jiu Li
authors.initials: JL
authors.lastname: Huang
authors.forename: Paul
authors.initials: P
authors.lastname: Nestel
authors.forename: Alex
authors.initials: A
authors.lastname: Agrotis
authors.forename: Alex
authors.initials: A
authors.lastname: Bobik
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000494:pharmacology*; D002339:Carotid Arteries / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002404:Catheterization / Q000009:adverse effects; D049109:Cell Proliferation / Q000187:drug effects*; D018932:Chemokine CCL2 / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004195:Disease Models, Animal; D006965:Hyperplasia; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism*; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: C542572:3,7-dihydroxyisoflav-3-ene; D000975:Antioxidants; D001578:Benzopyrans; D018932:Chemokine CCL2; D010982:Platelet-Derived Growth Factor; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; C075278:platelet-derived growth factor A; D013481:Superoxides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2